A number of acridinylaminomethanesulfonanilide derivatives have recently been studied for antitumour activity. AMSA or 4'-(9-acridinylamino) methanesulfonanilide was found to show high antitumour activity in L1210 leukaemia screening systems (see G. J. Atwell, B. F. Cain and R. N. Seelye, J. Med. Chem., 15, 611-615 (1972)). Of the derivatives of AMSA which have been studied, m-AMSA or 4'-(9-acridinylamino)-methanesulfon-m-anisidide has been shown to be highly effective in treating L1210 leukaemia and has shown promise in a number of other experimental tumour systems (see the following articles: B. F. Cain and G. J. Atwell, Europ. J. Cancer, 10, 539-549 (1974); B. F. Cain, G. J. Atwell and W. A. Denny, J. Med. Chem., 18, 1110-1117 (1975); B. F. Cain, W. R. Wilson and B. C. Baguley, Molecular Pharmacology, 12, 1027-1035 (1976); B. F. Cain, G. J. Atwell and W. A. Denny, J. Med. Chem., 19, 772-777 (1976); B. F. Cain and G. J. Atwell, J. Med. Chem., 19, 1409-1416 (1976); M. J. Waring Europ. J. Cancer, 12, 995-1001 (1976); B. C. Baguley, W. R. Wilson, L. R. Ferguson and B. F. Cain, Current Chemotherapy, pp. 1210-1212 (1978); W. A. Denny, G. J. Atwell and B. F. Cain, J. Med. Chem., 21, 5-10 (1978)).
m-AMSA has been selected for clinical trials and has generated clinical interest during Phase I and Phase II clinical studies (see D. D. Von Hoff and others, Cancer Treatment Reports, 62, No. 10, 1421-1426 (1978); S. S. Legha and others, Cancer Research, 38, 3712-3716 (1978) and B. F. Cain, U.S. patent application Ser. No. 151,927 and the literature articles numbered 22 to 58 referred to therein).
AMSA and m-AMSA have the structural formulae ##STR1## The antitumour activity of a large range of AMSA and m-AMSA analogs containing variously substituted acridine nuclei has now been investigated, see for example G. J. Atwell, B. F. Cain and R. N. Seelye, J. Med. Chem., 15, 611-615 (1972); B. F. Cain, R. N. Seelye and G. J. Atwell, J. Med. Chem., 17, 922-930 (1974); B. F. Cain, G. J. Atwell and W. A. Denny, J. Med. Chem., 18, 1110-1117 (1975), and J. Med. Chem., 19, 772-777 (1976); B. F. Cain and G. J. Atwell, J. Med. Chem., 19, 1124-1129 and 1409-1416 (1976); G. J. Atwell, B. F. Cain and W. A. Denny, J. Med. Chem., 20, 520-526, 987-996, 1128-1134, and 1242-1246 (1977); W. A. Denny, G. J. Atwell and B. F. Cain, J. Med. Chem., 21, 5-10 (1978); W. A. Denny and B. F. Cain, J. Med. Chem., 21, 430-437 (1978 ); B. F. Cain, B. C. Baguley and W. A. Denny, J. Med. Chem., 21, 658-668 (1978); L. R. Ferguson and W. A. Denny, J. Med. Chem., 22, 251-255 (1979) and W. A. Denny, G. J. Atwell and B. F. Cain J. Med. Chem., 22, 1453-1460 (1979).
As clinical cancer chemotherapy improves, and patients live symptom free for longer intervals, it is obviously important that the agents employed are not themselves carcinogenic and capable of disease re-induction. Employing mutagenicity in the Ames bacterial tester strains (B. N. Ames, J. McCann, and E. Yamasaki, Mutat. Res, 31, 347 (1975)) as likely predictors of carcinogenicity, it was apparent to the present inventors that mutagenic activity and antitumour effectiveness did not parallel one another. Such observations suggested that the undesirable side effect of mutagenicity might therefore be eliminated.
A new class of m-AMSA analogs containing a carboxamide substituent in the 3 and/or 5 positions in the acridine nucleus which have antitumour activity in animals and low or no direct mutagenicity, as described in our U.S. patent application Ser. No. 187,517. Included within that class of analogs is the compound ##STR2## (Compound 9 of Table 1 and Example B in Specification No. 187,517).